Dr. Craig Fletcher, a veterinarian, is in a structured postdoctoral fellowship program in Laboratory Animal Medicine and will continue to expand upon his scientific skills through unique integration of clinical training in comparative medicine and formal doctoral training. The purpose of this Mentored Clinical Scientist Development Award is to support a research program in cellular immunology and retroviral pathogenesis, which will culminate in both the Ph.D. degree and the opportunity for continued research experience. Dr. Fletcher's long-term goal is to become a principal investigator employing animal models to investigate the pathogenesis and therapy of HIV. The principal investigator's scientific training will be conducted in the Leukocyte Immunochemistry Laboratory at Johns Hopkins University, under the guidance of the sponsor Dr. James E. K. Hildreth. The candidate's training plan includes laboratory and didactic training in contemporary molecular techniques and research methods, applied to an animal model of AIDS. Preliminary work conducted by the principal investigator in the Hildreth's laboratory suggests that statins (lovastatin) inhibit HIV-1 and SIV infection and replication in vitro. The study design is aimed at understanding the mechanisms by which integrins and lipid rafts play a role in HIV and SIV biology in vitro. The three specific aims to be addressed are: (1) to determine if statins affect lipid raft formation thus alter the incorporation of integrins (and other cellular proteins) into HIV-1 virions; (2) to determine the impact of statin modulation of integrin and chemokine receptor function on HIV budding, entry, and virus-induced chemotaxis in vitro; (3) to determine if statins inhibit the spread of HIV and SIV in PBMC cultures by inducing apoptosis. Statins are among the most powerful cholesterol lowering drugs available and are widely prescribed around the world. Dyslipidemia and hypercholesteremia are prevalent conditions in patients with HIV infection on anti-retroviral therapy. In addition to this drug family's effect on cholesterol synthesis, investigators have recently found that statins directly inhibit the major a2 integrin, LFA-1. Given this dual effect of statins and the important role of LFA-1 and lipid rafts in the biology of HIV-1, these compounds represent a potentially important therapeutic and investigative tool for AIDS. The Department of Comparative Medicine of the Johns Hopkins University provides an ideal setting for training veterinarian-scientists and maximizes the potential for the principal investigator to establish a strong research foundation and develop into an independent investigator.